Drugs can often cause severe side effects and/or require multiple dosing regimens. Some of these side effects and inconvenient dosing regimens can be controlled or reduced by the use of improved formulations and/or improved delivery methods.
Paclitaxel, for example, is highly effective in treating breast and lung cancers by inhibiting the growth of cancer cells by binding to microtubules. However, because the drug has a low aqueous solubility, paclitaxel is typically formulated using the toxic solvent Cremophor® EL (polyoxyethylated castor oil), which limits the amount of drug that can be administered to a patient. Patients taking the drug often require premedication with steroids or antihistamines for hypersensitivity reactions caused by the solvent.
Abraxane®, a new paclitaxel formulation, does not employ a toxic solvent. When formulated with human serum albumin, the drug can be suspended in aqueous media. Thus, patients can better tolerate higher paclitaxel doses (up to 260 mg/m2 vs. 175 g/m2) and thereby achieve an improved response rate.
Doxorubicin is another highly effective cancer drug belonging to a class of anthracycline compounds. However, the drug can cause severe cardiotoxicity and death. Patients taking a cumulative dose of 300 mg/m2 have a 1-2% chance of developing cardiomyopathy, with the incidence increasing with increasing dose (400 mg/m2, 3-5%; 450 mg/m2, 5 to 8%; 500 mg/m2, 6-20%). The use of Doxil®, a pegylated liposomal formulation of doxorubicin, results in a reduced incidence of cardiotoxicity. Doxil® has a half-life in the blood of about 50 hours compared to about 10 minutes for doxorubicin. The slow-release of doxorubicin may explain the lower toxicity of the Doxil® formulation. Myocet®, a non-pegylated liposomal formulation of doxorubicin, also reduces the incidence of cardiotoxicity. Furthermore, its use also reduces the incidence of hand-foot syndrome associated with Doxil®. Myocet® is approved in Europe and is being evaluated in the United States.
Mitoxantrone is used for the treatment of acute non-lymphocytic leukemia. It is also indicated for reducing neurologic disability and/or the frequency of clinical relapses in patients with secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis (MS). Although one of the most effective drugs for treating MS, mitoxantrone is not recommended for long-term use. Patients who exceed a cumulative dose of 140 mg/m2 have an increased risk of acquiring irreversible cardiotoxicity and death. There is no liposomal formulation of this drug.
Bleomycin, in combination with other chemotherapeutic agents, is effective in treating squamous cell carcinoma, non-Hodgkin's lymphoma, and testicular carcinoma. However, patients taking a cumulative dose of 400 units (˜400 mg) risk developing pulmonary fibrosis.
Mertansine, a derivative of maytansine, is an experimental cytotoxic agent. Because of its extreme toxicity, it is not used as a stand-alone therapeutic agent. To minimize side effects and to maximize efficacy, the compound is conjugated to tumor-targeting monoclonal antibodies such as lorvotuzumab and trastuzumab.
Vedotin, an auristatin, is another potent cytotoxic agent. To minimize side effects and to maximize efficacy, it is conjugated to tumor-targeting monoclonal antibody brentuximab.
Recombinant interferon alfa-2a (Roferon® A) is used for the treatment of chronic hepatitis C, hairy cell leukemia, and chronic myelogenous leukemia. The recommended dosing regimen for Roferon® A for the treatment of chronic hepatitis C is three times per week administered subcutaneously for 12 months.
Pegasys®, a pegylated formulation of interferon alfa-2a, requires less frequent dosing. The recommended dosing regimen for Pegasys® for treating chronic hepatitis C is once weekly for 48 weeks by subcutaneous administration.
Zalbin®, an interferon alfa-2b conjugated to human serum albumin, is an alternative to unconjugated interferon alfa-2b (Intron® A). Instead of subcutaneously or intramuscularly dosing the non-conjugated drug three times a week for up to 24 months, Zalbin® is administered only once every two weeks.
Enfuvirtide, an FDA-approved HIV drug, is a fusion inhibitor having a linear 36-amino acid synthetic peptide. Due to its short half-life of four hours, treatment requires twice-daily subcutaneous injections. This inconvenient dosing schedule discourages its widespread use.